A recent study published in The Journal of Nutrition found that a polyphenol-rich tomato extract marketed as Fruitflow by Royal DSM was associated with significant reductions in fasting levels of trimethylamine N-oxide (TMAO) in blood and urine, signifying a reduction in a risk marker for adverse cardiovascular events.

According to the authors, the mechanism of action likely had to do with changes in the gut microbiome induced by the ingredient.

The randomized, double-blind, placebo-controlled crossover study was completed by 22 overweight and obese adults aged 35-65 years, who took a daily dose of the polyphenol-rich extract for four weeks. Stool, blood, and urine samples were collected to assess changes in plasma TMAO as well as fecal microbiota, metabolites, and urine TMAO.

Compared to the control group, which saw no changes, significant reductions in urine (-19.1 μM) and plasma (-1.5 μM) TMAO were observed in the Fruitflow group, as well as a significant reduction in plasma lipopolysaccharides.

These changes were correlated to changes in microbial beta-diversity—but not alpha-diversity—which were also observed in the treatment group. Lower levels of Bacteroides, Ruminococcus, and Hungatella were found in the treatment group. These three strains are known for their involvement in TMAO metabolism.

As a result, the authors concluded that Fruitflow may reduce TMAO levels by beneficially modulating the gut microbiota.

TMAO and Gut-Heart Axis

TMAO is created when TMA is absorbed by the intestinal epithelium and transported to the liver. TMA is a microbial metabolite produced in the gut from dietary phosphatidylcholine and L-carnitine, the latter of which is commonly found in red meat, cheese, and eggs, and was once thought to be a waste product of choline metabolism.

TMAO is emerging in clinical research as a biomarker associated with cardiovascular disease. It is also associated with intestinal permeability and low-grade inflammation. Lipopolysaccharides are also known to increase intestinal permeability. Altered gut microbiota are thought to be a common cause of both increased TMAO and lipopolysaccharides.

Fruitflow supplementation resulted in reductions in both TMAO and lipopolysaccharides in subjects in this study, along with increases in beta-diversity of gut microbiota. As such, the researchers concluded that the polyphenol-rich ingredient induced beneficial changes in the gut leading to reductions in these two biomarkers.

The plant polyphenols from Fruitflow are considered prebiotic candidates that are largely unable to be absorbed in the small intestine. But they undergo biotransformation in the colon by gut microbiota. With TMAO dependent on metabolism by the intestinal microbiota, gut microbiome strategies have emerged in the prevention of cardiovascular disease.

“DSM is committed to helping people improve their gut health and use this as a gateway to overall wellbeing,” said Dr. Robert E. Steinhart, principal scientist at DSM. “The results of this study are incredibly encouraging and support earlier findings that polyphenol-rich extracts can lower TMAO concentrations through a targeted and beneficial modulation of the gut microbiota. We’re looking forward to working with our customers to develop new dietary supplement solutions targeting the gut-heart axis. Looking ahead, this study paves the way for future research into the gut-brain axis, especially age-related cognitive decline. This is an exciting time for gut health research.”

“We’re still learning about how TMAO interacts with the body and how it exerts its effects,” said Ruedi Duss, global marketing manager at DSM. “However, what is apparent is the convincing evidence for its involvement in inflammation, cardiovascular disease, and obesity. Researchers have shown that high levels of TMAO may increase the risk of clot-related events like heart attacks and strokes. As such, TMAO is strongly associated with proatherogenic effects.”

Duss noted that the TMAO reduction observed in the group of participants taking Fruitflow aligns with other studies on polyphenol-rich natural products, and helps set the stage for future research examining the relationship between TMAO and health outcomes.

“Similar studies exploring the effect of polyphenols have observed comparable results, demonstrating the reproducibility of these findings,” Duss said. “A recent and much larger cross-sectional study investigating TMAO levels found they were significantly higher in patients with acute ischemic stroke compared to healthy controls. The researchers found a 1 μM/L increase in TMAO was associated with a 1.13-point increase in the National Institutes of Health Stroke Scale. Taking these findings into consideration, the data from our study are likely of clinical relevance as the mean decrease in plasma TMAO levels in the Fruitflow group was 1.51 μM, which would have clinical ramifications based on the National Institutes of Health Stroke Scale.”

Polyphenols have a host of other known activities, Duss noted, such as decreasing platelet aggregation, which reduces blood clot risk. They also regulate enzyme activities and modulate gene expression and intracellular signaling, therefore possessing antioxidant, immunomodulatory, and inflammatory modulating properties. “With regard to the effect of polyphenols on TMAO levels, I consider this an independent effect of the already well-established influence of Fruitflow on platelet aggregation,” Duss said.

While polyphenol-rich products often have some overlap in activity, each product or ingredient should be treated as unique, Duss noted. “Fruitflow contains more than 30 active components which makes it unique. The bioactive compounds in Fruitflow can be divided into groups based on their structures. The first comprises nucleosides such as adenosine, and the remainder fall into different classes of polyphenols; a range of compounds based on cinnamic and benzoic acids form the second group (such as chlorogenic acid), while the third group contains mainly flavonoid derivatives such as a family of quercetin compounds.”